Effectiveness of initiating treatment with valsartan/hydrochlorothiazide in patients with stage-1 or stage-2 hypertension

This prospective, 6-week, multicenter, double-blind study examined the benefits of initiating treatment with combination valsartan/hydrochlorothiazide (HCTZ) compared with initial valsartan monotherapy for 648 patients with stage-1 or stage-2 hypertension (age=52.6±10 years; 54% male; baseline blood pressure (BP)=161/98 mm Hg, 32% stage 1). Patients were randomized to valsartan 80 mg (V-low), valsartan 160 mg (V-high) or valsartan/HCTZ 160/12.5 mg (V/HCTZ), and electively titrated after weeks 2 and 4 to the next dosage level (maximum dose valsartan/HCTZ 160/25 mg) if BP remained >140/90 mm Hg. At end of the study, patients initiated with V/HCTZ required less titration steps compared with the initial valsartan monotherapy groups (63 vs 86% required titration by study end, respectively) and reached the target BP goal of <140/90 mm Hg in a shorter period of time (2.8 weeks) (P<0.0001) vs V-low (4.3 weeks) and V-high (3.9 weeks). Initial combination therapy was also associated with higher BP control rates and greater reductions in both systolic and diastolic BP from baseline (63%, −27.7±13/–15.1±8 mm Hg) compared with V-low (46%, −21.2±13/−11.4±8 mm Hg, P<0.0001) or V-high (51%, −24.0±13/−12.0±10 mm Hg, P<0.01). Overall and drug-related AEs were mild to moderate and were similar between V/HCTZ (53.1 and 14.1%, respectively) and the two monotherapy groups, V-low (50.5 and 13.8%) and V-high (50.7 and 11.8%). In conclusion, initiating therapy with a combination of valsartan and low-dose HCTZ results in early, improved BP efficacy with similar tolerability as compared with starting treatment with a low or higher dose of valsartan for patients with stage-1 and stage-2 hypertension

Calcium Channel Blockers, More than Diuretics, Enhance Vascular Protective Effects of Angiotensin Receptor Blockers in Salt-Loaded Hypertensive Rats

The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB

Efficacy of fixed-dose amlodipine and losartan combination compared with amlodipine monotherapy in stage 2 hypertension: a randomized, double blind, multicenter study

<p>Abstract</p> <p>Background</p> <p>The objective of this trial was to compare the blood-pressure lowering efficacy of amlodipine/losartan combination with amlodipine monotherapy after 6 weeks of treatment in Korean patients with stage 2 hypertension.</p> <p>Results</p> <p>In this multi-center, double-blind, randomized study, adult patients (n = 148) with stage 2 hypertension were randomized to amlodipine 5 mg/losartan 50 mg or amlodipine 5 mg. After 2 weeks, patients with systolic blood pressure (SBP) > 140 mmHg were titrated to amlodipine 10 mg/losartan 50 mg or amlodipine 10 mg. After 4 weeks of titration, hydrochlorothiazide 12.5 mg could be optionally added to both groups. The change from baseline in SBP was assessed after 6 weeks. The responder rate (defined as achieving SBP < 140 mmHg or DBP < 90 mmHg) was also assessed at 2, 6 and 8 weeks as secondary endpoints. Safety and tolerability were assessed through adverse event monitoring and laboratory testing. Baseline demographics and clinical characteristics were generally similar between treatment groups. Least-square mean reduction in SBP at 6 weeks (primary endpoint) was significantly greater in the combination group (36.5 mmHg vs. 31.6 mmHg; p = 0.0117). The responder rate in SBP (secondary endpoints) was significantly higher in the combination group at 2 weeks (52.1% vs. 33.3%; p = 0.0213) but not at 6 weeks (p = 0.0550) or 8 weeks (p = 0.0592). There was no significant difference between groups in the incidence of adverse events.</p> <p>Conclusion</p> <p>These results demonstrate that combination amlodipine/losartan therapy provides an effective and generally well-tolerated first line therapy for reducing blood pressure in stage 2 hypertensive patients.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01127217">NCT01127217</a></p

Preferential benefits of nifedipine GITS in systolic hypertension and in combination with RAS blockade: further analysis of the ‘ACTION' database in patients with angina

A retrospective analysis of the database from A Coronary Disease Trial Investigating Outcome with Nifedipine (ACTION) evaluated the effectiveness of nifedipine gastrointestinal therapeutic system (GITS) (i) in combination with renin angiotensin system (RAS) blockers and (ii) in patients with isolated systolic hypertension (ISH). Analysed on an intention-to-treat basis, treatment groups were compared by the log-rank test without adjustment for covariates and hazard ratios with 95% CIs were obtained using Cox proportional hazards models. Of 7665 randomized patients, 1732 patients were receiving RAS blockade at baseline, the addition of nifedipine GITS significantly reduced any cardiovascular (CV) event (−20% P<0.05), the composite of death, any CV event and revascularization (−16% P<0.05) and coronary angiography (−22% P<0.01). These benefits were achieved with relatively small differences in systolic (3.2 mm Hg) and diastolic blood pressure (BP) (2.3 mm Hg). In 2303 patients (30.0%) who had ISH at baseline (1145 nifedipine GITS and 1158 placebo), nifedipine significantly reduced the primary efficacy end point (−18% P<0.03), any CV event (−22% P<0.01) and new heart failure (−40% P<0.01). The benefits were associated with between-group differences in achieved BP of 4.7 and 3.3 mm Hg for systolic and diastolic BP, respectively. In summary, the lowest CV event rates were seen in those receiving (i) the combination of RAS blockade and nifedipine GITS and (ii) in those specifically treated for ISH

Long-term efficacy of a combination of amlodipine and olmesartan medoxomil±hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial

A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML)+ olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged ⩾65 and <65 years, Blacks and non-Blacks and patients with and without type 2 diabetes. After an 8-week double-blind, placebo-controlled portion of the study, patients initiated therapy on AML 5+OM 40 mg per day, were uptitrated stepwise to AML 10+OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged ⩾65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML+OM±HCTZ was efficacious, safe and well tolerated by these subgroups

24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension

To determine the effectiveness and safety of once-daily combination therapy with amlodipine, valsartan and hydrochlorothiazide for reducing ambulatory blood pressure (ABP) in patients with moderate to severe hypertension, a multicenter, double-blind study was performed (N=2271) that included ABP monitoring in a 283-patient subset. After a single-blind, placebo run-in period, patients were randomized to receive amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg), valsartan/hydrochlorothiazide (320/25 mg), amlodipine/valsartan (10/320 mg) or amlodipine/hydrochlorothiazide (10/25 mg) each morning for 8 weeks. Efficacy assessments included change from baseline in 24-h, daytime and night time mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Statistically significant and clinically relevant reductions from baseline in all these parameters occurred in all treatment groups (P<0.0001, all comparisons versus baseline). At week 8, least squares mean reductions from baseline in 24-h, daytime and night time mean ambulatory SBP/DBP were 30.3/19.7, 31.2/20.5 and 28.0/17.8 mm Hg, respectively, with amlodipine/valsartan/hydrochlorothiazide; corresponding reductions with dual therapies ranged from 18.8–24.1/11.7–15.5, 19.0–25.1/12.0–16.0 and 18.3–22.6/11.1–14.3 mm Hg (P⩽0.01, all comparisons of triple versus dual therapy). Treatment with amlodipine/valsartan/hydrochlorothiazide maintained full 24-h effectiveness, including during the morning hours; all hourly mean ambulatory SBP and mean ambulatory DBP measurements were ⩽130/85 mm Hg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period

Olmesartan/amlodipine vs olmesartan/hydrochlorothiazide in hypertensive patients with metabolic syndrome: the OLAS study

We studied the effects of treatment with olmesartan/amlodipine and olmesartan/hydrochlorothiazide on inflammatory and metabolic parameters (including new-onset diabetes as a secondary endpoint) in non-diabetic hypertensive patients with metabolic syndrome (MetS). A total of 120 patients with MetS and stage I and II hypertension were randomized to olmesartan 20 mg/amlodipine 5 mg or olmesartan 20 mg/hydrochlorothiazide 12.5 mg. If target systolic blood pressure (<140 mm Hg) was not reached, doses were doubled after 13 weeks; doxazosin 4 mg was added after 26 weeks, and doubled after 39 weeks; follow-up ended at 78 weeks. At each visit, blood pressure (BP), fasting plasma glucose, insulin, adiponectin, tumour necrosis factor-α, C-reactive protein (CRP), intercellular adhesion molecule-1, vascular cell adhesion molecule-1, interleukins-1β, -6 and -8, and albuminuria were measured; BP was similarly reduced in both groups; 80% of patients reached target BP. Reductions in albuminuria were also similar (50%). Only olmesartan/amlodipine reduced the insulin resistance index (24%, P<0.01), increased plasma adiponectin (16%, P<0.05) and significantly reduced all of the inflammation markers studied, except CRP, which showed a similar reduction in each group. The risk of new-onset diabetes was significantly lower with olmesartan/amlodipine (P=0.02). Both olmesartan-based combinations were effective, but the amlodipine combination resulted in metabolic and anti-inflammatory effects that may have advantages over the hydrochlorothiazide combination

Combination therapy in hypertension: An update

Meticulous control of blood pressure is required in patients with hypertension to produce the maximum reduction in clinical cardiovascular end points, especially in patients with comorbidities like diabetes mellitus where more aggressive blood pressure lowering might be beneficial. Recent clinical trials suggest that the approach of using monotherapy for the control of hypertension is not likely to be successful in most patients. Combination therapy may be theoretically favored by the fact that multiple factors contribute to hypertension, and achieving control of blood pressure with single agent acting through one particular mechanism may not be possible. Regimens can either be fixed dose combinations or drugs added sequentially one after other. Combining the drugs makes them available in a convenient dosing format, lower the dose of individual component, thus, reducing the side effects and improving compliance. Classes of antihypertensive agents which have been commonly used are angiotensin receptor blockers, thiazide diuretics, beta and alpha blockers, calcium antagonists and angiotensin-converting enzyme inhibitors. Thiazide diuretics and calcium channel blockers are effective, as well as combinations that include renin-angiotensin-aldosterone system blockers, in reducing BP. The majority of currently available fixed-dose combinations are diuretic-based. Combinations may be individualized according to the presence of comorbidities like diabetes mellitus, chronic renal failure, heart failure, thyroid disorders and for special population groups like elderly and pregnant females